Missing pieces of the puzzle: How glucagon-like peptides can improve our understanding of diabetes

Missing pieces of the puzzle: How glucagon-like peptides can improve our understanding of diabetes

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By: Mohammad-Masoud Zavvarian

Despite significant advances made in managing diabetes over the past century, there are still looming questions about its pathophysiology and the molecular mechanisms involved. With a worldwide increase in diabetes prevalence and its risk factors, such as obesity, it is becoming even more crucial to examine these questions (1). Taking up this challenge is Dr. Daniel Drucker, who has spent more than three decades investigating the role and clinical relevance of glucagon-like peptides (GLPs) and other proglucagon-derived peptides (PGDPs) in diabetes. His research has demonstrated that these hormones are essential regulators of various homeostatic processes in the body. Trained as a clinician in molecular endocrinology, Dr. Drucker became interested in the bioactivity of glucagon and GLPs early in his career. He published a foundational article in 1987 regarding the impacts GLP1 on insulin production (2), thereby opening new possibilities in diabetes research.

Diabetes is characterized by insufficient insulin activity, either through lack of insulin production or insulin resistance. Insulin is responsible for reducing blood glucose level and opposes the action of another pancreatic hormone called glucagon. Protecting the body from hypoglycemia, glucagon is transcribed from the proglucagon gene, which also codes for glucagon-like peptides—GLP1 and GLP2. The presence of prohormone convertase 2 (PG2) in the pancreatic α-cells makes the necessary post-translational modifications to convert proglucagon into glucagon. Conversely, the intestinal prohormone convertase (PG1) results in the conversion of proglucagon into GLP1, GLP2, glicentin, oxyntomodulin, and two intervening peptides (Figure 1). Dr. Drucker’s pioneering research—through genetic knockouts and pharmaceutical interventions—demonstrates that GLP1 plays a critical role in multiple target tissues (Figure 1). In particular, GLP1 is an important regulator of appetite, by targeting hypothalamic satiety centers. It also acts on the islet β-cells and α-cells in a glucose-dependent manner to promote insulin and inhibit glucagon secretion. GLP1 has also been shown to affect cardiovascular function. These properties make GLP1 a suitable candidate for diabetes treatment (3).

“Our lab’s goal is trying to understand the hormones’ action; hormones made in the gut, their synthesis and action. We have stayed very focused. We are looking at glucagon, GLP1, GLP2, gastric inhibitory polypeptide, and dipeptidyl peptidase IV. We want to understand how they work, and what therapeutic potentials might be there,” said Dr. Drucker.

His extensive research on these hormones was crucial for the development of new classes of medication for diabetes as well as short bowel syndrome (SBS), a gastrointestinal disorder also influenced by GLPs levels. For the treatment of diabetes, these medications are mainly aimed at increasing GLP-1 activity (4). It is important to note that although administration of GLP-1 reduces the serum glucose level, these peptides are degraded rapidly in the body by the enzyme dipeptidyl peptidase IV. As such, Dr. Drucker’s team focused on inhibitors of dipeptidyl peptidase IV, which has proved to be an effective treatment for diabetes patients because of its effects on GLP-1 stabilization, which ultimately helps to lower blood glucose level.

Dr. Drucker’s team is also studying an alternative therapeutic method involving activation of GLP1-receptors, which has been shown to enhance insulin biosynthesis, increase β-cell proliferation, restore β-cell sensitivity to glucose, reduce apoptosis, and ultimately expand the β-cell mass. Since β-cells are responsible for production of insulin, their enhancement would be a great strategy for diabetes treatment. For instance, extendin 4 (an agonist of the GLP1-receptor), which has been heavily investigated by Dr. Drucker’s team, has gained FDA approval as a treatment for type 2 diabetes (3).

For his exceptional work in diabetes research and short bowel syndrome (SBS), Dr. Drucker was elected as a Fellow of the Royal Society of Canada, an award granted to individuals that have made remarkable contributions in 2015. That year he also received the recognition of Officer of the Order of Canada, established by Her Majesty Queen Elizabeth II to recognize outstanding achievement, dedication to the community, and service to the nation. These are in addition to numerous domestic and international recognitions and awards granted for his vigorous and valuable contributions to diabetes research. When asked to comment on his accomplishments, Dr. Drucker stated, “Everything we work on has either become a drug for diabetes, obesity, or gastrointestinal disease, but more research is required to further understand the mechanism behind their actions.”

Dr. Drucker’s research and accomplishments are inspiring to many students and scientists in his field. According to Dr. Drucker, the most significant challenge faced by early-career researchers is to remain focused and driven. “My advice to younger scientists is to surround yourself with lots of mentors, and learn from the path they have traveled,” said Dr. Drucker. “Some will be very critical, and some might be supportive. But it is important not to allow negative drums to prevent you from trying.” Of utmost importance, he added, is the “realization that there is no harm in trying and failing, but that is a much better path than never trying.” Dr. Drucker remembers that as a clinician his path to laboratory research was faced with great obstacles. He was confronted with dissuading messages from his peers that his scientific endeavors would be faced with a low success rate. Yet, he endured the discouragements by surrounding himself with great mentors, and today he has become an internationally recognized scientist on diabetes research. When asked to comment about the role of the Institute of Medical Science in his success, Dr. Drucker replied that Toronto has benefited by having an inclusive system of hospitals and an academic institution. However, he added that having only one faculty of medicine has removed the necessary competitiveness in clinical research.

Dr. Drucker believes that the future of diabetes research will benefit from a more comprehensive understanding of PGDPs and their receptors. The discoveries made thus far have greatly influenced our understanding of diabetes and its concomitant gastrointestinal or cardiovascular complications. However, there are still many questions to be answered. It is thus essential for both institutions and scientists to build upon the findings that have already been made, pursuing one of the pillars of scientific discovery: incremental research.

References:

  1. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS medicine. 2006;3(11):e442.
  2. Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proceedings of the National Academy of Sciences. 1987;84(10):3434–3438.
  3. Drucker DJ. Biologic actions and therapeutic potential of the proglucagon-derived peptides. Nature Clinical Practice Endocrinology & Metabolism. 2005 Nov;1(1):22–31.
  4. Drucker DJ. The Cardiovascular Biology of Glucagon-like Peptide-1. Cell Metabolism. 2016 Jul;24(1):15–30.